1. Technical Field of the Invention
This invention relates to a new crystalline and anhydrous form of doxazosin mesylate, a process for its preparation and pharmaceutical compositions comprising this new Form II.
2. Description of the Prior Art
1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-1,4-benzodioxin-2- yl)carbonyl]piperazine monomethanesulfonate, the INN name of which is doxazosin mesylate, is a diaminoquinazolyl derivative of the class of the .alpha..sub.1 -receptor blockers and has the structural formula ##STR1## It shows a great structural similarity to the older representatives of this class, prazosin hydrochloride and terazosin hydrochloride. Whereas the two latter active substances are used primarily only in the treatment of high blood pressure, in the case of doxazosin mesylate, there is an additional indication, namely, the treatment of benign prostate hyperplasia.
Unlike prazosin and terazosin, doxazosin is used therapeutically not as the hydrochloride but as the mesylate, that is, as a salt of methanesulfonic acid.
Although medicaments containing doxazosin mesylate are already on the market, doxazosin mesylate has not hitherto been described. Even U.S. Pat. No. 4,188,390, which discloses doxazosin for the first time, does not contain a description of doxazosin mesylate. Only doxazosin monohydrochloride is described in the examples in that publication.
Because of its extremely sparing solubility in water, however, the hydrochloride is unsuitable for pharmaceutical purposes.
Attempts to prepare doxazosin mesylate in the conventional ways prove to be very difficult and lead to unsatisfactory results. On the one hand, doxazosin base is sparingly soluble in the solvents commonly used for forming salts. It is sufficiently soluble only in polar, aprotic, high-boiling solvents such as, for example, dimethylformamide. In these solvents, however, the solubility of doxazosin mesylate is similar to that of the base, so that the yields of mesylate obtained are totally unsatisfactory. Moreover, from the pharmacological aspect, dimethylformamide is a critical residual solvent in medicinally active substances. The current ICH guideline for residual solvents in pharmaceutical active substances ("ICH Guideline: Residual Solvents," Pharmeuropa, Vol. 8, No. 1, page 103, March 1996) places dimethylformamide in Class 2 as a solvent having known toxicity and limits the permissible residual content of the solvent to 500 ppm.
On the other hand, a second standard method for forming salts also fails because of the particular properties of doxazosin base and its salts. Doxazosin base can be dissolved in weak acids such as, for example, acetic acid, and in this phase can be subjected to clarification filtration for the removal of insoluble foreign particles which is indispensable for a pharmaceutical active substance, and afterwards the mesylate can be precipitated by adding methanesulfonic acid or a salt of methanesulfonic acid. When this procedure is carried out at room temperature, however, an unfilterable gel is obtained. If the procedure is carried out at more elevated temperatures, for example 50.degree. C., this gel agglomerates or, in higher concentrations, separates out as a second, non-solidifying oily phase. Through the addition of organic solvents such as, for example, acetone, the suction capacity of the precipitated doxazosin mesylate can be improved. However, drying of this product leads to the formation of lumps owing to the high moisture content, and impurities from the mother liquor, in particular coloring impurities, are included therein. Ultimately, a form of doxazosin mesylate is obtained which is shown by the X-ray spectrum to be amorphous and is moreover hygroscopic. Thermal analysis reveals an exothermic transformation at 200.degree. C. before the substance melts with decomposition at 267.degree. C.